Apparatus for modulation of effector organs

ABSTRACT

Modulation of target effector organs in vertebrate beings using direct current stimulation for stimulation of spinal cord at regions of autonomic innervation, using direct current for peripheral nerve stimulation, by modulating central autonomic outflow and combinations thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending U.S. application Ser.No. 15/190,080, filed Jun. 22, 2016, entitled APPARATUS FOR MODULATIONOF EFFECTOR ORGANS, which in turn is a continuation-in part ofco-pending U.S. application Ser. No. 15/046,797, filed Feb. 18, 2016,which is a continuation of U.S. application Ser. No. 14/579,829, filedDec. 22, 2014, now U.S. Pat. No. 9,283,391, which claims priority ofU.S. Provisional Application Ser. No. 62/092,214, filed Dec. 15, 2014,U.S. Provisional Application Ser. No. 61/925,423, filed Jan. 9, 2014,and U.S. Provisional Application Ser. No. 61/919,806, filed Dec. 22,2013. U.S. application Ser. No. 15/190,080 also claims priority to U.S.Provisional Application Ser. No. 62/183,045, filed Jun. 22, 2015. All ofthe foregoing are incorporated herein by reference in their entirety forall purposes.

FIELD

The present invention relates to method and apparatus for modulating andregulating autonomically-innervated effector organs, such as modulationand regulation of bladder function.

BACKGROUND

The nervous system includes the Central Nervous System (CNS) and thePeripheral Nervous System (PNS), the latter including the SomaticNervous System (SNS) and Autonomic Nervous System (ANS). The CNSincludes the brain and the spinal cord. The spinal cord is the maincommunication route for signals between the body and the brain. The SNSand ANS overlap the CNS and PNS. There are 31 pairs of spinal nervesarising from cervical (8), thoracic (12), lumbar (5), sacral (5) andcoccygeal (1) segments. The spinal nerves contain both sensory and motorfibers. Efferent nerves (as opposed to afferent nerves) are the nervesleading from the central nervous system to an effector organ, andefferent neural signals refer to neural signals from the brain that aretransmitted via spinal cord pathways to effector organs. Afferent nervesare the nerves leading to the central nervous system, and afferentneural signals refer to neural signals being transmitted to the brain.

The ANS consists of two divisions, the sympathetic nervous system andthe parasympathetic nervous system, FIG. 1, and is responsible forregulating bodily functions including heart rate, respiration,digestion, bladder tone, sexual response and other functions. Activationof the sympathetic nervous system results in preparation of the body forstressful or emergency situations, while activation of theparasympathetic nervous system results in conservation and restorationand controls body processes during normal situations. For specificorgans that are innervated by the autonomic nervous system, it is wellknown which spinal levels are involved. FIG. 2 shows segmentalsympathetic and parasympathetic innervation of various organs.Parasympathetic innervation is either through the vagus nerve (cranialnerve X) or at the sacral levels (S2-S4). Sympathetic preganglionicneurons either synapse in the sympathetic chain ganglia or projectthrough the sympathetic chain ganglia and synapse at various gangliasuch as superior mesenteric ganglia or inferior mesenteric ganglia. Thepost-ganglionic neuron then projects to the end organ that itinnervates. Parasympathetic pre-ganglionic neurons (from cranial nerve Xand below) synapse very close to the organ they innervate and usually ina nerve plexus attached to the organ, and synapse with a post-ganglionicneuron that sends projections to the organ. The autonomic nervous systemincludes both sensory and motor neurons.

The ability to activate or inhibit either the sympathetic orparasympathetic nervous system would enable the regulation of numerousbodily functions and enable the treatment of specific disorders relatedto dysfunction of either the sympathetic or parasympathetic system.Normal functions that are potentially regulated by modulation ofsympathetic or parasympathetic activity include modulatingbronchodilation in the airways, modulating vasoconstriction in the skinand organs, stimulating gluconeogenesis and glucose release from theliver, stimulating secretion of epinephrine and norepinephrine by theadrenal gland, modulation of sweating, slowing or increasing heartrateand pumping efficiency, modulating tidal volume and rate of respiration,slowing or increasing intestinal processes involved with digestion,modulating urine production, modulating bladder contraction, modulatingsphincter control, stimulating erection and sexual arousal, and numerousothers. Beyond modulating normal functions, there are numerous disordersof the ANS that have been described and are referred to asdysautonomias, and is due to failure or disruption of either thesympathetic or parasympathetic divisions of the ANS. Specific suchdisorders include autoimmune autonomic ganglionopathy, congenitalcentral hypoventilation syndrome, familiar dysautonomia, Holmes-Adiesyndrome, multiple system atrophy, Shy-Drager syndrome, neurallymediated syncope, orthostatic hypotension, postural tachycardiasyndrome, striatonigral degeneration and vasovagal syncope. Elevatedsympathetic tone has been linked to disorders such as heart failure,hypertension, obesity, obstructive sleep apnea, diabetes, migraine,parkinsonian symptoms, septic shock, primary hyperhidrosis, complexregional pain syndrome and numerous others.

As there are many disorders and dysfunctions associated with abnormalregulation of autonomically-innervated effector organs, the ability toregulate the autonomic nervous system would enable important newtherapeutic strategies. We have developed novel approaches to modulatingthe autonomic nervous system using various implementations oftrans-spinal direct current stimulation (tsDCS).

The bladder is one example of an autonomically controlled organ. Thebladder functions as a reservoir and is responsible for storing urinethat has been formed by the kidneys in the process of eliminatingmetabolites and excess water from the blood. The stored urine isreleased via the urethra in the process of micturition.

The pathways mediating neural control of bladder function are wellestablished and include sympathetic, parasympathetic and somaticpathways. Referring to FIG. 3, sympathetic control of the bladder isfrom sympathetic efferents from T11-L2 that run via the sympathetictrunk and the splanchnic nerves to the inferior mesenteric ganglion.Post-ganglionic fibers contribute to the hypogastric plexus and reachthe bladder where they synapse on the detrusor muscle, and also synapseon the sphincter vesicae at the bladder neck. Parasympathetic control isfrom parasympathetic fibers that arise from S2-S4 and travel via thepelvic splanchnic nerves to synapse on post-ganglionic neurons locatedin a dense plexus among the detrusor smooth muscle cells in the wall ofthe bladder. Post-ganglionic parasympathetic fibers cause contraction ofthe bladder detrusor muscle and relaxation of the sphincter vesicae. Theexternal urethral sphincter (EUS) consists of striated muscle and isunder voluntary control via alpha motor neurons in Onuf's nucleus in theventral horns of S2-S4. Afferent responses from bladder stretchreceptors enter the spinal cord at T11-L2 and also S2-S4 where theytravel up to brainstem areas. Sensory fibers in the urethral wallrespond to urinary flow by causing firing of their cell bodies locatedin dorsal root ganglia, which synapse on neurons in the spinal corddorsal horn. These sensory fibers travel to the spinal cord via thepudendal nerve, and transection of this sensory nerve reduces bladdercontraction strength and voiding efficiency.

Urinary retention is an inability to empty the bladder completely andcan be acute or chronic. Retention can be due to numerous issues,including constipation, prostatic enlargement, urethral strictures,urinary tract stones, tumors, and nerve conduction problems. Such nerveconduction problems are seen in brain and spinal cord injuries,diabetes, multiple sclerosis, stroke, pelvic surgery, heavy metalpoisoning, aging and idiopathically. These result in either weak bladdercontraction and/or excess sphincter activation. As such, modulationstrategies that enable improved emptying of the bladder are oftherapeutic interest.

Urinary incontinence is loss of bladder control leading to mild leakingall the way up to uncontrollable wetting. It results from weak sphinctermuscles, overactive bladder muscles, damage to nerves that control thebladder from diseases such as multiple sclerosis and Parkinson'sdisease, and can occur after prostate surgery. As such, modulationstrategies that treat urinary incontinence are of therapeutic interest.

Neurogenic bladder refers to bladder malfunction due to any type ofneurological disorder, which can include stroke, multiple sclerosis,spinal cord injury, peripheral nerve lesions and numerous otherconditions. Following a stroke, the brain often enters a cerebral shockphase, and the urinary bladder will be in retention (or detrusorareflexia). Around 25% of stroke patients develop acute urinaryretention. Following the cerebral shock phase, the bladder often showsdetrusor hyperreflexia, and the patient will have urinary frequency,urgency and urge incontinence. In multiple sclerosis, the most commonurological dysfunction is detrusor hyperreflexia, occurring in as manyas 50-90% of patients with MS. Detrusor areflexia is seen in 20-30% ofpatients, so treatment must be individualized based on urodynamicfindings. In spinal cord injuries occurring from motor vehicle or divingaccidents, an initial response of spinal shock is seen in which patientsexperience flaccid paralysis below the level of injury, and experiencesurinary retention consistent with detrusor areflexia. Spinal shock phaselasts usually 6-12 weeks but may be prolonged. During this period, theurinary bladder often must be drained with either intermittentcatheterization or an indwelling catheter. Following the spinal shockphase, bladder function returns, however with an increase inexcitability, and results in detrusor hyperreflexia. Peripheral nervelesions can be due to diabetes mellitus, herpes zoster, neurosyphilis,herniated lumbar disk disease, pelvic surgery and other conditions, andcan result in detrusor areflexia. There is a continuing and unmet needfor improved ability to impose beneficial control over behavior of endeffectors. Embodiments of the present invention are variously directedto meeting such need.

SUMMARY OF THE INVENTION

As there are many disorders and dysfunctions related to the nervoussystem, such as those associated with abnormal regulation ofautonomically-innervated effector organs, the ability to regulaterelated parts of the nervous system, such as the autonomic nervoussystem, enables new therapeutic strategies and interventions. Wedisclose novel systems, devices, apparatuses and methods for modulatingparts of the nervous systems using various implementations oftrans-spinal direct current stimulation (tsDCS) and we provide newtherapeutic strategies and interventions for modulation of bladder andother organs using trans-spinal direct current stimulation.

Therefore the present invention relates to methods and systems utilizingtrans-spinal direct current stimulation for modulation of targeteffector organs. Illustrative embodiments of this disclosure aredirected to application of tsDCS to modulation of effector constituentsof the autonomic nervous system (ANS), and illustrative embodimentsinclude method and apparatus for treatment of bladder dysfunctions. Suchdisclosure is by way of illustration and not by way of limitation of thescope of the present invention to other organs.

We apply tsDCS in various configurations. In some embodiments, we usetsDCS by itself. In other embodiments, we use coordinated multi-siteneurostimulation that incorporates tsDCS together with stimulation atother site(s) along the neural axis.

In a double-stimulation configuration, we provide simultaneous spinaltsDCS stimulation together with a second stimulation. In one embodimentwe provide tsDCS spinal stimulation combined with direct currentperipheral stimulation of a nerve leading to a targeted effector organ.In an alternative double-stimulation configuration, we providesimultaneous spinal stimulation together with a second stimulation thatmodulates central autonomic outflow.

In a triple-stimulation configuration, we provide simultaneousstimulation of cerebral, spinal and peripheral sites serving targeteffector organs, e.g., organs such as the bladder or external urethralsphincter (EUS). Through such coordinated multi-site neurostimulation,the descending cortical signals are amplified by spinal-level tsDCS todrive stronger responses at the target effector organ. This approacheffectively stimulates neural pathways and enables delivery of strongercortical signals to drive stronger effector responses.

In one embodiment, method and system for modulating function of theautonomic nervous system in a vertebrate being is provided, including aprimary stimulation component which initiates central autonomic outflow,and a second stimulation component which modulates descending autonomicpathways at the level of the spinal cord. A further embodiment includesa primary stimulation component that includes either transcranial directcurrent stimulation, transcutaneous vagal nerve stimulation,transcranial magnetic stimulation, cold/hot pressors, oral ortransdermal pharmaceutical agents, visual stimuli, auditory stimuli,olfactory stimuli or other forms of stimulation. In some embodiments,the secondary stimulation component comprises trans-spinal directcurrent stimulation and the autonomic outflow is either sympatheticoutflow or parasympathetic outflow.

A further method and system for modulating function of the autonomicnervous system in a vertebrate being is provided, including a primarystimulation component which initiates central autonomic outflow, asecond stimulation component which modulates descending autonomicpathways at the level of the spinal cord, and a third peripheralstimulation component which stimulates a nerve leading to a targeteffector organ.

In embodiments of the invention we incorporate a wearable tsDCScontroller that modulates descending autonomic signals traversing thespinal cord. In some embodiments, this is combined with an implantedelectrode that directly stimulates the nerve to a targeted effectororgan. The implanted electrode is in wireless communication with thewearable tsDCS controller. This stimulation is selected as eitherexcitatory or inhibitory in practices of the invention.

This approach is sufficient for certain applications. In otherapplications, it is beneficial to directly modulate central autonomicoutflow before spinal level modulation via tsDCS. In several practicesof the invention, we increase or decrease sympathetic outflow, orincrease or decrease parasympathetic outflow. Furthermore, in particularembodiments we provide non-invasive and non-pharmacological modulationof autonomic outflow for control and treatment of autonomically-relatedfunctions and disorders. In other embodiments, we providepharmacological modulation of autonomic outflow for control andtreatment of autonomically-related functions and disorders.

We apply tsDCS in various configurations. In embodiments of theinvention, the stimulation applied to the spine is a continuous constantcurrent direct current signal. For practical reasons, this constanttsDCS signal is ramped at the beginning and end of application to reducelocal induced stimulation artifacts. In some embodiments this is apulsed signal which delivers an equivalent continuous constant-currentsignal to the stimulation site.

In various embodiments, the tsDCS spinal stimulation is applied with anactive electrode at the spine being driven as either anode or cathodeand cooperating with its complimentary return electrode to define thespinal circuit. The distal neural stimulation, sometimes referred to asperipheral direct current stimulation (pDCS) is applied with the distalactive electrode at a nerve to the target effector organ being driven aseither anode or cathode at the opposite polarity of the active spinalelectrode, and also cooperating with the distal complementary returnelectrode to define the distal peripheral circuit between theseelectrodes. These spinal and peripheral stimulation circuits areenergized and during such energized state create a resulting circuitbetween the active spinal electrode and the active neural electrode.This forms an active resulting anode-cathode pair, with the resultingcurrent flow between this energized pair during the stimulation periodfavorably polarizing the connecting neural pathway down to the nerve attarget effector organ. The result of applying such stimulation is tomodulate neural transmission from spinal cord to the target effectororgan, resulting in modulation of function at the target effector organ.

BRIEF DESCRIPTION OF THE DRAWINGS

The above illustrative and further embodiments are described below inconjunction with the following drawings, where specifically numberedcomponents are described and will be appreciated to be thus described inall figures of the disclosure:

FIG. 1 shows the two divisions of the Autonomic Nervous System: thesympathetic nervous system and the parasympathetic nervous system;

FIG. 2: shows segmental sympathetic and parasympathetic innervation ofvarious organs;

FIG. 3: shows well-known pathways mediating neural control of bladderfunction;

FIG. 4A: shows illustrative stimulator devices in practice ofembodiments of the invention;

FIG. 4B: shows common TMS magnetic stimulator with figure-eight probe inpractice of embodiments of the invention;

FIGS. 5A-C: show illustrative wearable and implantable components andconfigurations, including a closed-loop system, in practice ofembodiments of the invention;

FIG. 6A-B: shows surgical placement of cysostomy tube into the bladderto enable measurement of bladder pressures and urine output, in practiceof embodiments of the invention;

FIG. 7A: shows bladder pressures and the frequency of voiding andnon-voiding contractions measured at baseline prior to stimulation withcathodal tsDCS, in practice of embodiments of the invention;

FIG. 7B: shows spinal to bladder tsDCS stimulation that initiatedbladder retention and voiding reflex in a vertebrate being with severechronic spinal cord injury, in practice of embodiments of the invention;

FIG. 7C: shows bladder reflexes in subjects with acute complete spinalcord injury and the effects of tsDCS, in practice of embodiments of theinvention;

FIG. 8: shows treatment of patient with a condition of urinaryincontinence involving detrusor hyperreflexia treated by application oftsDCS in a configuration that decreases parasympathetic tone, inpractice of embodiments of the invention;

FIG. 9: shows return electrode is positioned within the bladdertrans-urethrally, in practice of embodiments of the invention;

FIGS. 10 and 11: show a subject with a condition of urinary incontinencetreated by application of tsDCS in a configuration that increasessympathetic tone with an anodal return electrode abdominally positionedanteriorly (FIG. 10) and at an and with the return electrode positionedwithin the bladder trans-urethrally (FIG. 11), in practice ofembodiments of the invention;

FIG. 12 shows spinal stimulations which increase parasympathetic outflowto the bladder combined with electrical stimulation of theparasympathetic preganglionic fibers in pelvic nerve, with cathodaltsDCS applied at S2-S4, in practice of embodiments of the invention;

FIG. 13: shows spinal stimulations which increase parasympatheticoutflow to the bladder combined with electrical inhibition of thepudendal nerve that innervates the EUS using implanted electrodes, withcathodal tsDCS applied at S2-S4, in practice of embodiments of theinvention;

FIG. 14: shows spinal stimulations which increase parasympatheticoutflow to the bladder combined with electrical stimulation of thepudendal nerve using implanted electrodes, with cathodal tsDCS appliedat S2-S4, in practice of embodiments of the invention;

FIG. 15: shows cathodal spinal stimulations increase sympathetic outflowto the bladder combined with implanted microstimulator electrodes whichstimulate the pudendal nerve, with cathodal spinal stimulations atT11-L2, in practice of embodiments of the invention;

FIG. 16: shows cathodal spinal stimulations which increase sympatheticoutflow to the bladder combined with implanted electrodes which areapplied to inhibit the parasympathetic preganglionic fibers of thepelvic splanchnic nerves, with cathodal spinal stimulations at T11-L2,in practice of embodiments of the invention;

FIG. 17: shows non-invasive tDCS coupled with tsDCS at the relevantspinal level to modulate autonomic outflow, with sympathetic outflowfrom the brain increased by anodal tDCS over the primary motor cortexand further increased at the spinal level of the targeted effector organby cathodal tsDCS at the high thoracic level, in practice of embodimentsof the invention;

FIG. 18A-B: shows transcutaneous vagal nerve stimulation (tVNS) and anembodiment where auricular stimulation is combined with a wearable tsDCScontroller, in practice of embodiments of the invention;

FIG. 19: shows pharmacological autonomic modulators, in practice ofembodiments of the invention; and

FIG. 20: shows a triple-stimulation approach in practice of embodimentsof these teachings, in practice of embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The description is not to be taken in a limiting sense, but is mademerely for the purpose of illustrating the general principles of theseteachings, since the scope of these teachings is best defined by theappended claims.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

The following definitions pertain to the present disclosure, with theunderstanding that such may be modified by context of use. For purposesof the teaching of the present teachings:

The term “nerves” may be referred to herein as including nerves,neurons, motor neurons and interneurons and the like, and are generallyreferred to herein as “nerves” or “neurons”;

The terms or concepts of nerve stimulation and neural stimulation areused liberally and interchangeably to describe applications of thestimulation of the teachings;

The terms neuromodulation, modulation, stimulation and regulation areused interchangeably as equivalents for purposes of this disclosure andindicate an effect imposed upon a target in practice of presentteachings;

The terms dysfunction, disorder, defect and abnormality are usedinterchangeably as equivalents for purposes of this disclosure andindicate the concept of medically recognized conditions suitable formedical intervention:

The term effector organ refers to a neurally-innervated organ thatproduces an effect in response to nerve stimulation. Muscles areincluded within such definition for purposes of this disclosure. Theeffects of stimulation of the present teachings upon an effector organor muscle may be discussed interchangeably for purposes of inclusivediscussion of the present teachings.

The term “stimulation,” as used herein, refers to either excitation orinhibition of nerve fibers, also referred to as up regulation or downregulation.

The term “electrical stimulation,” as used herein refers to theproduction or introduction of current into spinal nerve, neuron, circuitor pathway, whether by applying a voltage or magnetically inducing acurrent.

Improved method and apparatus for neuromodulation and regulation ofeffector organs are disclosed herein below.

In practice of embodiments of the invention, we provide benchtop,wearable or implantable systems for modulating the components of thenervous system, including effector organs. Strategies that providespinal stimulation via tsDCS (mono-stimulation), spinal stimulation viatsDCS combined with either peripheral stimulation or stimulation ofcentral autonomic outflow (double-stimulation), and spinal stimulationvia tsDCS combined with peripheral stimulation and stimulation of cortex(e.g., motor cortex) or central autonomic outflow (triple-stimulation),are disclosed. In illustrative embodiments herein, we disclose methodsand apparatus that apply these strategies to modulate the autonomicnervous system and to regulate autonomically-innervated effector organssuch as the bladder. These strategies treat nervous system conditions,including bladder incontinence and bladder retention.

In practice of embodiments of the invention, we provide benchtop,wearable or implantable systems for modulating the components of thenervous system, including effector organs. Strategies provide spinalstimulation by applying tsDCS on its own (mono-stimulation), or tsDCSspinal stimulation combined with peripheral stimulation(double-stimulation), or tsDCS spinal stimulation combined with cerebralstimulation (double-stimulation), or tsDCS spinal stimulation combinedwith two other stimulations, which may include peripheral stimulationand cerebral stimulation (triple-stimulation), are disclosed. Inillustrative embodiments herein, we disclose methods and apparatus thatapply these strategies to modulate the autonomic nervous system and toregulate autonomically-innervated effector organs such as, but notlimited to, the bladder. These strategies treat nervous systemconditions, including bladder incontinence and bladder retention.

FIG. 4A shows illustrative stimulator devices 10, 12, 14 which may beutilized in various practices of the invention. These devices include atsDCS stimulation device 10 which may be used on its own to deliver atsDCS mono-stimulation treatment or in combination with additionalstimulation devices 12 and/or 14 to provide various double and triplestimulation treatments, in several embodiments of the invention.

tsDCS stimulator device 10 delivers trans-spinal direct currentstimulation to a spinal location neurally associated with a distaleffector organ of interest, and more particularly associated withfunction of a target effector organ, such as the bladder. In variousembodiments the stimulation supplied by stimulator device 10 providesmonopolar, and an essentially or effectively continuous, constant,non-varying direct current stimulation of a selected polarity, in arange of 0.5 to 5 or 6 mA, typically 1-4.5 mA. Stimulator device 10illustrates a tsDCS component in embodiments of the invention. In thisillustration, device 10 includes a computing and synchronizing unit 16,for provision of a system control function, and including a signalpolarity and function controller 18, and having a system memory 19. Thesecond stimulator device 12 provides a known transcranial direct current(tDCS) stimulation source of pulsed or constant direct currentstimulation to the cortex area C, having a circuit 20 for signalcomputing and synchronizing, and for control of signal polarity andfunction, integrated with resident memory 19. In an alternativeembodiment, repetitive pulsed magnetic stimulation (rTMS) is provided tothe cortical area C by a TMS magnetic stimulator 12A using afigure-eight probe 22, as shown in FIG. 4B, as will be understood by aperson skilled in the art.

In an illustrative embodiment, pulsed electrical stimulation of themotor cortex in an adult ranges at 100-400 mA, typically around 200 mA,pulse width of 100-300 microseconds, typically around 200 ms, 0.5 to 3Hz repetition rate, operating voltage 400-800. For a child, 70-100milliamps at 100 microseconds is a target. Magnetic stimulation isalternatively applied, and in an illustrative pulsed TMS embodiment,magnetic stimulation is delivered at a rate of 0.5 to 3 Hz, 200microsecond pulse width, reaching stimulation current levels equivalentto the electrical stimulation, as will be understood by a person skilledin the art. In one TMS practice of the invention, rTMS is applied with amagnetic flux density of 1.0 to 1.5 Tesla.

The third stimulator device 14 is a source of direct current stimulationto stimulate a peripheral location of interest, typically forstimulation of a nerve leading to a target effector organ of interest,such as the bladder, and which may include non-varying or pulsed directcurrent stimulation. This stimulator device 14 includes a circuit 23 forsignal computing and synchronizing and for control of signal polarityand function, with resident memory. An illustrative peripheral constantdirect current stimulation is applied at levels of 1-5 mA for doublestimulation and with pulsed peripheral intensity typically ranges isfrom 5 to 40 mA for triple stimulation. In a bladder treatment of theinvention, continuous tsDCS is applied to the Onuf's nucleus in thesacral region of the spinal cord, with typical intensity in the rangefrom 1-4.5 mA.

All three of devices 10, 14, 12, are shown having an I/O component forexternal signal connection, such as with electrodes, 24, 26, 30, 32, and34, 36, respectively, providing +/− terminals for electrode connection.Each unit is also provided with a communication component 40, whichenables data links 42 for wired or wireless communication between thedevices or with other external devices. In this illustration, all threedevices 10, 12, 14 have a user interface with microprocessor unit 44 anda power supply P, such as rechargeable batteries.

The tsDCS stimulator device 10 is engaged on its own when tsDCSmono-stimulation is provided. For double stimulation, the tsDCSstimulator device 10 is engaged along with another stimulation source,such as provided by the cortical stimulator device 12 in one practice orby the peripheral stimulator device 14 in another practice of theinvention. In one practice double-stimulation is provided by twoindependent or isolated circuits with the same or paired stimulationdevices.

As will be appreciated by a person skilled in the art, in severalembodiments, where constant current stimulation is to be delivered tothe patient, the two cooperating stimulation sources, such as devices 10and 14 share a common ground in order to enable an efficient controlfunction as the circuits attempt to maintain assigned signal levels overtime in the presence of changing resistance of the current path(s)within the patient.

In some embodiments, the tsDCS stimulator device 10 is engaged toprovide tsDCS in a triple-stimulation embodiment, in cooperation withother two stimulation sources, such as with the cortical stimulatordevice 12 and the peripheral stimulator device 14. In an illustrativeembodiment, the tsDCS triple-stimulation includes pulsed stimulation atthe cortex, constant stimulation at the spine and pulsed stimulation atthe peripheral location.

Referring to FIG. 4A, a person to be treated is shown from the back.Three sets of electrode connections are shown as would be used during anillustrative triple stimulation practice of the invention. Electrodeswill be applied in locations discussed below.

As an illustration only, in a tsDCS triple stimulation embodiment, thecortical stimulator 12 provides transcortical direct current (tDCS)stimulation as a source of direct current to the local cortical area Cvia active cortical electrode 34 and return (also called “reference”)electrode 36. The stimulation path 34-36 is defined between the twoelectrodes to stimulate the local cortex area C which is associated withthe intended stimulation of a target effector organ of interest, such asbladder 21 (indicated by dotted symbol). In an alternative embodiment,repetitive pulsed magnetic stimulation (rTMS) is supplied to corticalarea C by a probe 22 of a TMS magnetic stimulator 12A shown in FIG. 4B,for application of known pulsed cortical stimulation, as will beunderstood by a person skilled in the art.

The tsDCS stimulator 10 delivers trans-spinal direct currentmono-stimulation to a spinal location 15 associated with neural outflowassociated with a target effector organ, such as at the bladder. Thespinal active electrode 24 is applied at spinal location 15 and a returnelectrode 26 is located distal to the spinal area, such as at ananterior aspect of the body. In this embodiment, a spinal stimulationcircuit 17 is defined between these two electrodes with the stimulationcurrent traversing the spinal processes at that location as astimulation path of interest.

The third stimulator 14 provides peripheral direct current stimulationto stimulate a nerve leading to a target effector organ or a nerve ofthe target effector organ, such as the bladder 21. In one embodiment,the stimulation signal is monopolar and pulsed. In another embodimentthe stimulation signal is monopolar and constant.

An illustrative embodiment of the invention includes method and systemhaving a single tsDCS stimulation circuit, for mono-stimulation of thespinal cord, and defined by placing an electrode at the spinal locationof interest and a return electrode on the anterior aspect of the body,thus defining a pathway of interest between these electrodes. In variouspractices of the invention, these electrodes are assigned as eitheranode or cathode and a tsDCS stimulation circuit is thus created forapplying current between the electrodes and for modulating spinal cordexcitability. The applied current is delivered having a desired signalcharacter and level. In further embodiments of the invention, we applythese teachings in wearable and implantable embodiments.

In a further embodiment of the invention, a wearable mono-stimulationdevice is provided. In this practice, there are two electrodes which areskin surface type, serving as the active spinal electrode and the spinalcircuit return electrode. In one embodiment, a surface of the wearabledevice provides the spinal electrode and the device also connects to areturn electrode, on the opposite side of the spinal cord, which isplaced on the skin surface such as on the abdomen or iliac crest. Inanother embodiment, the reference electrode is placed internal to thebladder, such as by urethral catheter insertion, surgically, or thelike. The spinal location of interest is selected based on spinaloutflow to the target effector organ. In another implantablemono-stimulation device of the invention, there are two electrodes whichare implantable electrodes, serving as the active spinal electrode andthe return electrode. In one embodiment, the mono-stimulation device isfully implantable, with electrode leads from the device to dorsal spinallocation and ventral location tunneled subcutaneously. The spinallocation of interest is selected based on spinal outflow to the targeteffector organ.

In a fully implantable subcutaneous double-stimulation embodiment of theinvention, two circuits are supplied by four leads emanating fromcontroller device. This embodiment delivers two simultaneousstimulations, a spinal stimulation and a peripheral stimulation appliedto a nerve of the target effector organ. There are two separatestimulation current paths with these two circuits. But these circuitsalso interact to form a resulting stimulation current path between theactive electrode at the spine of the spinal circuit and the electrode ofopposite polarity positioned at the nerve of the target effector organ.This provides a polarization flow down along the neural path between thetwo described electrodes. In this double stimulation embodiment, thefirst current path is a tsDCS spinal circuit defined by placing anactive spinal electrode at the spinal location of interest and a returnelectrode at a non-spinal location, with the applied current runningbetween these electrodes. The second current path is a peripheralcircuit defined by placing active and return electrodes on or inproximity to a nerve of the target effector organ.

In a further embodiment, a two-part semi-implantable stimulation deviceis provided. A first component is a wearable mono-stimulation devicewhich includes an active spinal electrode applied by skin attachment anda return electrode. The second component is an implanted peripheralstimulator or microstimulator with two leads that has its own powersupply. Both leads of the second component are in contact with or inclose proximity to a nerve of a target effector organ. The wearablecomponent can communicate wirelessly with the implanted component. Whenthe wearable component turns on and issues its stimulation signal, theimplanted stimulator responds and issues a stimulation signal to thetarget effector organ, which can be either excitatory or inhibitory.

In a further embodiment of a wearable double-stimulation device, twocircuits are supplied by four leads emanating from controller device.This embodiment delivers two simultaneous stimulations. The firststimulation is a spinal stimulation delivered via active spinalelectrode applied by skin attachment and a return electrode. The secondstimulation modulates central autonomic outflow, and can be eithertrans-cranial direct current stimulation (tDCS) or trans-cutaneous vagalnerve stimulation (tVNS). There are two separate stimulation currentpaths with these two circuits but they are electrically isolated fromeach other.

In a further embodiment, a two-part semi-implantable stimulation deviceis provided. A first component is a wearable double-stimulation devicethat provides a first stimulation that is spinal stimulation, and asecond stimulation that modulates central autonomic outflow. The secondcomponent is an implanted peripheral stimulator or microstimulator withtwo leads that has its own power supply. Both leads of the secondcomponent are in contact with or in close proximity to a nerve of atarget effector organ. The wearable component can communicate wirelesslywith the implanted component. When the wearable component turns on andissues its stimulation signal, the implanted stimulator responds andissues a stimulation signal to the target effector organ, which can beeither excitatory or inhibitory.

Illustrative embodiments of the invention is set forth in FIG. 5A-Cfeaturing wearable and implantable components.

In FIG. 5A, a disk-shaped wearable system 100 is disclosed. Asillustrated in FIG. 5A-B, system 100 includes a wearable/implantabletsDCS controller 102, shown affixed to the patient at its skin-side 104optionally presenting an electrode surface 111. External interactionwith controller 102 is by buttons or touch screen or by wirelessinteraction with a portable device or cell phone 103 for userintervention. Controller 102 directs action of implanted control unit106.

Controller 102 incorporates a cognate circuit of device 10, FIG. 4A,including a miniaturized version of computing and synchronizing unit 16,with memory 19, for provision of system control, and further including asignal polarity and function controller 18, with appropriate instructionloaded set in memory 19 for instruction of implanted control unit 106.Control unit 106 includes a rechargeable power supply (not shown), andaccording to instructions from controller 102, applies electricalstimulation to a local peripheral nerve 108 that innervates a targeteffector organ, such as the bladder. The stimulation can be adjusted asneeded, and is provided as constant continuous non-varying directcurrent stimulation, or can be pulsed direct current stimulation, invarious practices of the invention.

In one embodiment, the implanted control unit 106 provides electricalleads 109 to deliver the stimulation signal to suitable electrode, shownas a cuff electrode 110, which is affixed at nerve 108. In oneembodiment, controller 102 presents an electrode surface 111 on the skinside of the device for affixation of the device to the patient. Thiselectrode surface 111 may include electrically conductive adhesive toassist attachment to the patient, and permits application of tsDCSstimulation at that location. In further embodiments of the invention,system 100 further includes and cooperates with the implanted controlunit 106, which in turn drives single or multiple implanted electrodes,such as a cuff electrode 110 via leads 109. Cuff electrode 110 is placedaround a peripheral or autonomic nerve of interest 108 and stimulatesthe nerve fibers to achieve either excitation or inhibition of theeffector organ, e.g., bladder. The cuff electrode 110 is made of soft,flexible materials such as silicone that render an electrode flexibleand less prone to injure the peripheral nerve than common electrodes.Alternatively, two electrode leads representing the anode and cathodeare positioned in contact with or in close proximity to the nerve 108.

In another embodiment of the present teachings, a wearable tsDCS unitthat wirelessly controls an implanted stimulator is combined with asensor that detects a relevant physiological state to form a closed-loopsystem. The wearable tsDCS unit wirelessly communicates with the sensor,which could be either implanted or wearable, and activates tsDCS spinalstimulation and stimulation of an effector organ via the implantedstimulator, when it detects a relevant state. The sensor can beconfigured to detect blood pressure, heart rate, body temperature,respiration rate, skin turgor, skin conductivity, oxygenation state,bladder pressure, urine osmolarity, hemodynamic parameters, specificcardiac rhythms by EKG, urethral pressure, anal sphincter pressure,muscle contraction state by EMG, specific brain waves by EEG,electrolytes, specific proteins and signaling molecules in specifictissue compartments, blood glucose concentration, gastric pH,gastrointestinal motility sounds, environmental cues such as specificsights, sounds and signals, and other parameters depending on intendedapplication. The neuromodulation system is thus activated upon sensing aspecific state, and inactivated when that state no longer holds. In oneembodiment of the present teachings, the system also includes a sensorconfigured to detect a predetermined parameter, such as those listedherein above, and configured to provide a sensed value of thepredetermined parameter to the controller component. The controllercomponent is further configured to initiate stimulation, initiation ofstimulation determined by whether the sensed value is less than orexceeds a predetermined value denoting the specific state.

A closed loop system 200 of the invention is shown in FIG. 5C and isconfigured to operate autonomously in the background with reduced userinteraction. As will be appreciated by a person skilled in the art, thesystem 200 takes advantage of modern wireless communications, as shown,which is available to implanted medical systems. System 200 includestsDCS controller 102 and implanted control unit 106 with implantedelectrode 110 at nerve 108, and including an implanted feedback device112. The feedback device 112 is in wireless communication withcontroller 102, which then responsively instructs control unit 106 toadjust or initiate or cease the stimulation function as needed. Theimplanted stimulator, control unit 106, stimulates nerve 108 via leads109 and electrode 110, consistent with instructions from controller 102.

In a bladder management embodiment, the implanted feedback device 112 isa bladder pressure sensor 112A. Bladder data from sensor 112A iswirelessly provided to controller 102 which wirelessly instructsimplanted control unit 106, or directly instructs control unit 106, tocontrol stimulation of bladder nerve 108 via electrode 110, to reduceincontinence or to reduce urinary retention, for example.

Controller unit 102 has human interface, common instruction memorystore, and logic circuits, and or a microprocessor, for executing itscontrol instructions to control unit 106. In turn, the control unit hasa power supply which supplies the electrode accordingly. Preferably thepower supply is wirelessly rechargeable.

The implanted sensor 112A closes the loop with the device controllercircuit 102 in system 200 such that the system automatically adjustswithout user intervention, according to stored profiles. In oneembodiment of bladder modulation, the implanted sensor 112A is a bladderfunction sensor such as a bladder pressure sensor which detects bladderpressure exerted by urine volume in the bladder and enables andwirelessly informs the needed neural stimulation instruction to beissued from controller 102 to control unit 106 to initiate stimulationand to obtain a desired outcome, such as controlled voiding. In oneembodiment, the data from bladder sensor 112A is directly acted upon bycontrol unit 106.

In a further application of the closed-loop system 200 of FIG. 5C, wecombine stimulation that modulates central autonomic outflow, in which aprimary stimulation modulates either the sympathetic or parasympatheticbranch of the autonomic nervous system, with the closed-loop system 200.Thus, cerebral and spinal stimulations are combined with an implantedstimulator that is under the control of the wearable tsDCS controller.

It will be appreciated that embodiments of the present teachings featuretsDCS spinal stimulation. In many embodiments, this tsDCS stimulation isaugmented with stimulation of a peripheral nerve leading to a targeteffector organ. In practices of these teachings, peripheral directcurrent stimulation (pDCS) is continuous, non-varying, steady-statedirect current stimulation, while in other embodiments, stimulation of aperipheral nerve or autonomic nerve fiber associated with an effectororgan may include pulsed electrical stimulation, continuous DCS, pulsedDCS, or other alternating signals. The present teachings also may bepracticed with wireless microstimulators as known in the art.

In practice of the invention, we apply tsDCS in various configurations.A tsDCS stimulation system provides tsDCS stimulation, which in variousembodiments is applied by itself to favorably polarize a target neuralpathway of interest. In other embodiments, we use coordinated multi-siteneurostimulation that incorporates the tsDCS polarizing stimulationtogether with stimulation at other site(s) along the neural axis. Weprovide this multi-site stimulation by combination of tsDCS stimulationwith at least one other stimulation, which includes cerebral stimulationand/or peripheral stimulation.

In one embodiment of the present teachings, peripheral stimulation iscontinuous steady-state and non-varying. In another embodiment of theinvention, excitation or inhibition of a stimulated autonomic nervefiber depends on the frequency of the applied electrical stimulation. Inone illustrative but non-limiting practice of the invention, inhibitionof parasympathetic fibers is achieved with high-frequency monopolarelectrical stimulation (greater than about 50-100 Hz), while excitationof parasympathetic fibers is achieved with low-frequency monopolarelectrical stimulation (less than about 50-100 Hz). Similarly,inhibition of sympathetic fibers is achieved with high-frequencyelectrical stimulation (greater than about 50-100 Hz), while excitationof sympathetic fibers is achieved with low-frequency electricalstimulation (less than about 50-100 Hz). In various embodiments we applystimulation via skin surface electrodes in a range up to about 1-6 mA ormore often at 1-4.5 mA.

In embodiments of the present teachings, the tsDCS device is fullyimplantable, with electrode leads from the device to dorsal spinallocation and ventral location tunneled subcutaneously. Electrode leadsfrom the tsDCS device which function for peripheral stimulation are alsotunneled subcutaneously with electrodes implanted on the appropriatenerves of the effector organ being modulated. In another embodiment, thetsDCS device remains external to the body and wearable, but haselectrode leads for peripheral stimulation that are either surfacemounted or implanted.

Illustrative Mono-Stimulation Embodiments

It will be appreciated that the mono-stimulation process involvesapplying a single source of constant current stimulation and istypically delivered by the tsDCS stimulator alone. In practice of thepresent invention, we employ tsDCS to induce either an area of increasedor decreased neural activation within the spinal cord.

The present invention teaches methods and systems utilizing trans-spinaldirect current stimulation for modulation of body functions, such as ateffector organs. Illustrative embodiments of this disclosure aredirected to application of such tsDCS to modulation of effectorconstituents of the autonomic nervous system (ANS). Illustrativeembodiments include method and apparatus for treatment of bladderdysfunctions. This disclosure is by way of illustration and not by wayof limitation of the scope of the present invention.

It will now be appreciated that in various practices of the invention,tsDCS stimulation is applied at the spinal location. At peripheral sites(or cerebral sites in the case of transcutaneous vagus nervestimulation), stimulation can be of a broader variety within the scopeof the invention. In several practices of the present invention,monopolar direct current stimulation is applied at specific points alongthe neural axis. Monopolar direct current electrical stimulation isapplied and characterized as anodal or cathodal. In an embodiment of theinvention, this characterization is indicative of the polarity of thecurrent source as applied between a spinal location of interest and areturn location. Depending upon the desired outcome, the circuit may beapplied as anodal, positive, at the location of interest, and cathodal,negative, at the return location, or vice versa.

Single and/or multiple monopolar direct current stimulation circuits areengaged in various embodiments. These monopolar stimulations are,characterized as being anodal or cathodal, have a polarizing effect overthe stimulated pathways. This polarization has significant favorablemodulatory effect upon the transmission efficiency of neural signalsflowing over a neural pathway of interest. Monopolar stimulation appliedto a neural pathway has potential polarizing and modulatory affects. Invarious practices of the invention, we engage and harness these effectsaccordingly.

In an illustrative embodiment of the invention in awake healthy mice, atwo-electrode mono-stimulation configuration of tsDCS was utilized,employing a stimulator, with an active cathode electrode on thelumbosacral spine (L6-S3), and a return anode electrode on the abdomen.To enable measurements of bladder function, we surgically placed acysostomy tube (PE50 tubing) into the bladder to enable measurement ofbladder pressures and urine output (FIG. 6). Bladder pressures, and thefrequency of voiding and non-voiding contractions were measured atbaseline prior to stimulation with cathodal tsDCS (FIG. 7A). In suchembodiments with cathodal tsDCS providing stimulation, there is adecrease in the basal pressure, increase in the amplitude of bladdercontractions, increase in inter-voiding contraction interval, andincrease the number and amplitude of non-voiding contractions. In aseries of experiments, after 20 minutes of cathodal tsDCS, these effectswere still apparent. With such stimulation, the bladder can contractmore fully.

The same stimulation paradigm was also evaluated in awake mice withchronic spinal cord injury, with spinal cord lesioning at T10 level 30days prior to stimulation studies. In these subjects, there is excessivebladder activity and non-voiding contractions, with higher bladderpressures as compared to healthy subjects, a condition of detrusorhyperreflexia. Baseline measurements were done in these subjects,followed by measurements during cathodal tsDCS, and 2 hours after 20minutes of cathodal tsDCS. In awake subjects with chronic spinal cordinjury, there is a decrease in the basal pressure, larger non-voidingcontractions, and a decreased frequency of voiding contractions. Similarto awake healthy subjects, cathodal tsDCS enables the bladder ofsubjects with chronic spinal cord injury to contract more fully.

In another embodiment relating to treatment of chronic spinal cordinjury in mice, a two-electrode configuration of tsDCS was utilized,with an anodal electrode on the lumbosacral spine (L6-S3), and with, inone embodiment, the return electrode on the front of the subject'sabdomen, and in another embodiment, with the return electrode at thebladder wall via transurethral insertion. FIG. 7B shows spinal tobladder tsDCS stimulation that initiated bladder retention and voidingreflex in a vertebrate being with severe chronic spinal cord injury. Thesubject had demonstrated skin irritation caused by excessive urinationdue to inability to retain urine. The top provides cystometry tracesshowing intravesicle pressure before, during, and after stimulation withanode on the spine and cathode inside the bladder. Note that there wereno reflexes before or after stimulation. Traces on the right are withexpanded time scale to show the structure of the reflexes. The bottomtrace shows cystometry traces from the same subject showing before,during stimulation 1 (anode inside the bladder), stimulation 2 (cathodeinside the bladder), and after. An improved ability to retain urine isseen even after stimulation is switched off.

In further studies of mice with acute spinal cord injury, the sametwo-electrode configuration of tsDCS was utilized. In acute spinal cordinjury, there is spinal shock and detrusor areflexia, during whichperiod the bladder fills to high and potentially dangerous pressures,with voiding pressures significantly higher than normal subjects or insubjects with chronic spinal cord injury. This represents a significanthealth issue because it can cause stretch injuries to the bladder andupper urinary tract complications.

FIG. 7C shows bladder reflexes in subjects with acute complete spinalcord injury and the effects of tsDCS. Baseline reflexes show very highvoiding pressures that were further increased by spinal anode/cathode inbladder arrangement. This effect was maintained for at least 10 minafter the current was turned off. When the polarity was switched, withspinal cathode and anode in bladder, this configuration immediatelydecreased the voiding pressure and decreased inter-voiding contractioninterval, demonstrating that this configuration has therapeuticallyuseful effects in subjects with detrusor areflexia following acutespinal cord injury.

These results are consistent with both normal and spinal cord injuredmammals. Excitability of small or moderate sized spinal neurons isincreased by cathodal tsDCS and depressed by anodal tsDCS. Sinceautonomic preganglionic neurons are smaller in size, they follow thisprinciple. We have found that cathodal tsDCS on the lumbosacral regionincreases the excitability of spinal parasympathetic preganglionicneurons hence decreasing urine storage reflexes and increasing voidingreflexes. Reverse polarity induces opposite modulation, i.e., increasingurine storage reflexes and decreasing voiding reflexes. In suchpractices, we have found that placing the return electrode inside oraround the bladder enhances modulatory effects.

The described anodal spinal/cathodal bladder configuration is effectivein delaying the bladder voiding reflex to allow for longer filling time.Moreover, the same arrangement produces efficient voiding that isevident in lowering the basal pressure after each voiding cycle. In anillustrative embodiment of the invention, this anodal spinal/cathodalbladder configuration has an inhibitory effect on the parasympatheticinput to the bladder. Inhibiting the parasympathetic inputs causesrelaxation of the bladder detrusor and contraction of the sphinctervesicae. This allows for longer inter-voiding contraction interval. Inaddition, this configuration enables increased sympathetic influenceover parasympathetic. This treatment is valuable in for achievingconditions of low pressure storage and efficient bladder voiding. Infurther practices of the invention, we treat conditions of detrusorareflexia by switching the polarities of the electrodes applied tospinal and bladder locations.

In practice of the present invention, a patient with a condition ofurinary incontinence involving detrusor hyperreflexia is treated byapplication of tsDCS in a configuration that decreases parasympathetictone, FIG. 8. Such a decrease in parasympathetic tone results inrelaxation of the detrusor contraction and increased contraction of thesphincter vesicae. In one embodiment this is non-invasively achieved byanodal tsDCS at the level of S2-S4 with a return cathodal electrodepositioned anteriorly at an abdominal location, such as the skinsuperior to the iliac bone. In another embodiment, the return electrodeis positioned within the bladder trans-urethrally, FIG. 9. In furtherpractice of the invention these polarities (i.e., the anodal andcathodal assignments,) are reversed for treatment of conditions ofurinary retention. In this embodiment, the configuration results in anincrease in parasympathetic tone.

In further embodiments of the present invention, a subject with acondition of urinary incontinence is treated by application of tsDCS ina configuration that increases sympathetic tone, FIG. 10. Such anincrease in sympathetic tone results in relaxation and expansion of thedetrusor muscle, constriction of the sphincter vesicae, and inhibitionof parasympathetic nerves that trigger bladder contraction. This isnon-invasively achieved by cathodal tsDCS at the T11-L2 spinal levelwith an anodal return electrode positioned anteriorly at an abdominallocation. In variant of the embodiment, FIG. 11, the return electrode ispositioned within the bladder trans-urethrally. In further practice ofthe invention these polarities (i.e., the anodal and cathodalassignments,) are reversed for treatment of conditions of urinaryretention, which achieves a decrease of sympathetic tone.

An embodiment of the invention includes method and system having asingle tsDCS stimulation circuit, for mono-stimulation of the spinalcord, and defined by placing an electrode at the spinal location ofinterest and a return electrode on the anterior aspect of the body, thusdefining a pathway of interest between these electrodes. In variouspractices of the invention, these electrodes are assigned as eitheranode or cathode and a tsDCS stimulation circuit is thus created forapplying current between the electrodes and for modulating spinal cordexcitability. The applied current is delivered having a desired signalcharacter and level.

In a wearable mono-stimulation device embodiment of the invention, thereare two electrodes which are skin surface type, serving as the activespinal electrode and the return electrode. In one embodiment, thesurface of the wearable device provides the spinal electrode and thedevice also connects to a return electrode on the opposite side of thespinal cord, which is placed on the skin surface such as on the abdomenor iliac crest. In another embodiment, the reference electrode is placedinternal to the bladder, such as by urethral catheter insertion,surgically, or the like. The spinal location of interest is selectedbased on spinal outflow to the target effector organ.

In an implantable mono-stimulation device of the invention, there aretwo electrodes which are implantable electrodes, serving as the activespinal electrode and the return electrode. In one embodiment, themono-stimulation device is fully implantable, with electrode leads fromthe device to dorsal spinal location and ventral location tunneledsubcutaneously. The spinal location of interest is selected based onspinal outflow to the target effector organ.

Illustrative Double-Stimulation Embodiments

Beyond strategies that utilize spinal stimulation via tsDCS on its own,we also disclose strategies that combine spinal stimulation via tsDCSwith additional stimulation.

We teach double-stimulation in various embodiments. Illustrativeembodiments include two stimulators electrically tied together in assystem for polarizing a critical neural pathway; a wearablemono-stimulation device communicating wirelessly with an implantedmicrostimulator; and two separate stimulators that are electricallyisolated, as when there is a cortical stimulation using tDCS combinedwith spinal stimulation using tsDCS. Still other configurations willoccur consistent with this disclosure that are also within the scope ofthe invention.

In one double-stimulation embodiment of the invention, we providesimultaneous tsDCS spinal stimulation together with pulsed peripheraldirect current stimulation (pDCS) of a nerve leading to a targetedeffector organ. In one particular embodiment, a resulting polarizingcircuit is defined between an active spinal tsDCS stimulation circuitand an active pulsed pDCS peripheral stimulation circuit.

In one embodiment of the present invention, the described spinalstimulations which increase parasympathetic outflow to the bladder arecombined with electrical stimulation of the parasympatheticpreganglionic fibers in pelvic nerve, FIG. 12, with cathodal tsDCSapplied at S2-S4. Stimulation of the pelvic splanchnic nerve results incontraction of the bladder detrusor, and relaxation of the sphinctervesicae, thereby further treating a condition of urinary retention. Infurther practice of the invention, these polarities (i.e., the anodaland cathodal assignments,) are reversed for treatment of conditions ofurinary incontinence resulting in a decrease in parasympathetic tone.

Excessive activity in the somatic efferents innervating the striatedmuscle of the external urethral sphincter (EUS) results in contractionof the sphincter. In another embodiment of the present invention, thedescribed spinal stimulations which increase parasympathetic outflow tothe bladder are combined with electrical inhibition of the pudendalnerve that innervates the EUS using implanted electrodes, FIG. 13, withcathodal tsDCS applied at S2-S4. This combination results in contractionof the bladder detrusor, relaxation of the sphincter vesicae, andrelaxation of the EUS, thereby further treating a condition of urinaryretention. In further practice of the invention, these polarities (i.e.,the anodal and cathodal assignments,) are reversed for treatment ofconditions of urinary incontinence and the pudendal nerve innervatingthe EUS is electrically stimulated using implanted electrodes.

Stimulation of the sensory afferents that fire in response to urine flowthrough urethra results in increased strength of bladder contraction andvoiding efficiency. In another embodiment of the present invention, thedescribed spinal stimulations which increase parasympathetic outflow tothe bladder are combined with electrical stimulation of the pudendalnerve using implanted electrodes, FIG. 14, with cathodal tsDCS appliedat S2-S4.

In a further embodiment, cathodal spinal stimulations increasesympathetic outflow to the bladder as combined with implantedmicrostimulator electrodes which stimulate the pudendal nerve, FIG. 15,with cathodal spinal stimulations at T11-L2. Increased sympathetic toneresults in relaxation of the bladder detrusor and contraction of thesphincter vesicae, while stimulation of the pudendal nerve results incontraction of the external urethral sphincter, thereby further treatinga condition of urinary incontinence. In further practice of theinvention, these polarities (i.e., the anodal and cathodal assignments,)are reversed for treatment of conditions of urinary retention and thepudendal nerve innervating the EUS is electrically inhibited usingimplanted electrodes. In such embodiments, the implanted microstimulatorcommunicates with and is controlled by a tsDCS controller that providesspinal stimulations, that can be either a wearable device, or animplanted subcutaneous device.

In a further embodiment, the cathodal spinal stimulations which increasesympathetic outflow to the bladder are combined with implantedelectrodes which are applied to inhibit the parasympatheticpreganglionic fibers of the pelvic splanchnic nerves, FIG. 16, withcathodal spinal stimulations at T11-L2. Increased sympathetic toneresults in relaxation of the bladder detrusor and contraction of thesphincter vesicae, while inhibition of the pelvic splanchnic nervesresults in further relaxation of the bladder detrusor, thereby furthertreating a condition of urinary incontinence. In further practice of theinvention, these polarities (i.e., the anodal and cathodal assignments,)are reversed for treatment of conditions of urinary retention.

In a fully implantable subcutaneous double-stimulation embodiment of theinvention, two circuits are supplied by four leads emanating fromcontroller device. This embodiment delivers two simultaneousstimulations, a spinal stimulation and a peripheral stimulation appliedto a nerve of the target effector organ. There are two separatestimulation current paths with these two circuits. But these circuitsalso interact to form a resulting stimulation current path between theanode of one circuit (i.e., active electrode at the spine of the spinalcircuit) and the active cathode at the nerve of the neural circuit. Thisprovides a polarization flow down along the neural path between the twoactive electrodes. In this double stimulation embodiment, the firstcurrent path is a tsDCS spinal circuit defined by placing an activespinal electrode at the spinal location of interest and a returnelectrode at a non-spinal location, with the applied current runningacross the tissues between these electrodes. The second current path isa peripheral circuit defined by placing active cathode and anodeelectrodes on or in proximity to a nerve of the target effector organ.

In a further embodiment, a two-part semi-implantable stimulation deviceis provided. A first component is a wearable mono-stimulation devicewhich includes an active spinal electrode applied by skin attachment anda return electrode. The second component is an implanted peripheralstimulator or microstimulator with two leads that has its own powersupply. Both leads of the second component are in contact with or inclose proximity to a nerve of a target effector organ. The wearablecomponent can communicate wirelessly with the implanted component. Whenthe wearable component turns on and issues its stimulation signal, theimplanted stimulator responds and issues a stimulation signal to thetarget effector organ, which can be either excitatory or inhibitory.

In a further embodiment of a wearable double-stimulation device, twocircuits are supplied by four leads emanating from controller device.This embodiment delivers two simultaneous stimulations. The firststimulation is a spinal stimulation delivered via active spinalelectrode applied by skin attachment and a return electrode. The secondstimulation modulates central autonomic outflow, and can be eithertrans-cranial direct current stimulation (tDCS) or trans-cutaneous vagalnerve stimulation (tVNS). There are two separate stimulation currentpaths with these two circuits that are electrically isolated from eachother.

Triple-Stimulation Embodiments

We also herein describe strategies that combine spinal stimulation,peripheral stimulation, and stimulation of central autonomic outflow tomodulate autonomic function. The previously disclosed strategies basedon mono-stimulation and double-stimulation might be sufficient forcertain applications. In other applications, it will be necessary orbeneficial to directly modulate central autonomic outflow before spinallevel modulation via tsDCS and potential peripheral stimulation.Non-invasive methods for modulating central autonomic outflow arecombined with other sites of stimulation using a variety of approaches:

Transcranial direct current stimulation (tDCS)—A number of differenttDCS montages have been utilized to modulate the autonomic nervoussystem. Anodal tDCS over the primary motor cortex, with cathode returnelectrode over the contralateral supraorbital area has been reported toincrease sympathetic activity (Clancy et al., Brain Stim., 2014,7:97-104). Anodal stimulation of the left dorsolateral prefrontal cortex(DLPFC) has been reported to increase parasympathetic activity, whileanodal stimulation of the right DLPFC has been reported to increasesympathetic activity (Brunoni et al., Psychoneuroendocrinology, 2012).Other work has reported that anodal tDCS over the temporal lobe resultsin increased parasympathetic activity. As such, non-invasive tDCS can becoupled with tsDCS at the relevant spinal level to modulate autonomicoutflow. In one embodiment, sympathetic outflow from the brain isincreased by anodal tDCS over the primary motor cortex and furtherincreased at the spinal level of the targeted effector organ by cathodaltsDCS at the high thoracic level. This embodiment is shown in FIG. 17,where cortical electrodes are shown combined with a wearable tsDCScontroller. In another embodiment, sympathetic outflow from the brain isincreased by anodal tDCS of the right DLPFC and further increased at thespinal level of the targeted effector organ by cathodal tsDCS. In yetanother embodiment, parasympathetic outflow from the brain is increasedby anodal tDCS over the temporal lobe and further increased at eitherthe S2-S4 spinal level of the targeted effector organ or the brainstemlevel of DMV by cathodal tsDCS.

Transcutaneous vagal nerve stimulation (tVNS)—The auricular branch ofthe vagus nerve supplies sensation to the posterior parts of the earpinna, external auditory canal and tympanic membrane, FIG. 18A. Nervecell bodies are located in the superior (jugular) ganglion of the vagus,and they project to the nucleus of the tractus solitarius (NTS) in thebrainstem. Electrical stimulation of the ear concha (tVNS) producesactivation of NTS and its known projections (parabrachial nucleus,nucleus accumbens, hypothalamus, amygdala). The dorsal motor nucleus ofthe vagus (DMV) in the brainstem contains the cell bodies of theparasympathetic neurons that project down the vagus nerve aspreganglionic efferent fibers. Direct connections between the NTS andDMV have been described, and it is established that NTS sendsprojections to DMV. Stimulation of the external ear tragus usingelectrical stimulation (10-50 mA, 30 Hz pulse frequency, 200 microsecondpulse width) results in decreased sympathetic discharge (Clancy et al.,Brain Stim., 2014, 7:817-877. In a practice of the present invention, weutilize this non-invasive methodology for decreasing sympathetic toneand coupling it with anodal tsDCS at the spinal level. Sympatheticoutflow from the brain is reduced by tVNS and further reduced at thespinal level of the targeted effector organ by applied anodal tsDCS.This embodiment is shown in FIG. 18B, where auricular stimulation iscombined with a wearable tsDCS controller.

Transcranial magnetic stimulation (TMS)—TMS, both repetitive and singlepulse, has been utilized in studies that modulate the autonomic nervoussystem. Targeted sites include left temporo-parietal cortex (Lai et al.,2010) and primary motor cortex M1 (Vernieri et al., 2009 and Yozbatiranet al., 2009). TMS was found to exert changes on autonomic control inthese, and other studies. Accordingly, in a further embodiment wecombine TMS with tsDCS at the spinal level. While FIG. 17 is illustratedshowing cortical stimulation via tDCS, it will be appreciated that TMSis an alternative source of cortical stimulation in practices of thepresent invention.

Cold/hot pressors—It is known that immersion of a subject's hand in abucket of ice water results in increased heart rate and pulse pressure,thought to be due to increased sympathetic tone activated by sensoryafferents. As such, in practices of the invention, we utilize thisapproach as a methodology to initiate modulation of autonomic outflow.As a bucket of ice water is impractical, we utilize alternativemethodologies to achieve this effect. More specifically, in oneembodiment, this effect is delivered as a cooling/heating pad that isaffixed to a thermosensitive area of skin such as the upper back, or inanother embodiment is presented as a vest or glove with cooling/heatingelements. This device is switched to either “cold stimulation” or “hotstimulation” to provide that sensation to the skin. To increasesympathetic tone to a specific effector organ, we combine activation of“cold stimulation” to the subject's skin with cathodal tsDCS at therelevant spinal level. To increase parasympathetic tone to a specificeffector organ, we combine activation of “hot stimulation” to thesubject's skin with cathodal tsDCS at the S2-S4 level (or DMV brainstemlevel). In this way, efferent outflow through either the sympathetic orparasympathetic system is activated depending on which temperature“setting” is used, and cathodal tsDCS amplifies the signals that aregoing to autonomic neurons in the spinal cord.

Pharmacological autonomic modulators—Certain pharmacological agents havemodulatory effects on the autonomic nervous system. Sympathomimeticsincrease sympathetic tone, and include amphetamines and phenylephrine.Sympatholytics decrease sympathetic tone, and include prazosin andyohimbine. Parasympathomimetics increase parasympathetic tone, andinclude muscarine, pilocarpine and choline esters. Parasympatholyticsdecrease sympathetic tone, and include scopalamine and atropine.Sympathomimetics can be given in combination with parasympatholytics,and parasympathomimetics can be given in combination withsympatholytics. Depending on specific molecular characteristics, thesepharmacological agents can be given orally, subcutaneously,intramuscularly, transdermally, intravenously or as depot injections.Pharmacological autonomic modulators are shown in FIG. 19.

As will be understood by a person skilled in the art, in practices ofthe present invention, we modulate autonomic outflow and use variousstrategies to monitor effect. For example, in various embodiments, wemonitor readouts including heart rate, heart rate variability,microneurography recording muscle sympathetic nerve activity, bloodpressure, pulse pressure, pupillary size, skin conductance, sympatheticskin response, respiratory rate, cerebral vasomotor reactivity, and bodytemperature, the utility of which will be understood by a person skilledin the art.

In another embodiment, various of the above described approaches ofmodulating central autonomic outflow, is combined with spinalstimulation and is further combined with a third peripheral stimulation,delivered at the level of the nerve leading to the target effectororgan, to render a useful therapeutic effect. This triple-stimulationapproach is shown in FIG. 20.

In a further embodiment, a two-part semi-implantable stimulation deviceis provided. A first component is a wearable double-stimulation devicethat provides a first stimulation that is spinal stimulation, and asecond stimulation that modulates central autonomic outflow. The secondcomponent is an implanted peripheral stimulator or microstimulator withtwo leads that has its own power supply. Both leads of the secondcomponent are in contact with or in close proximity to a nerve of atarget effector organ. The wearable component can communicate wirelesslywith the implanted component. When the wearable component turns on andissues its stimulation signal, the implanted stimulator responds andissues a stimulation signal to the target effector organ, which can beeither excitatory or inhibitory.

In various embodiments, effector organ stimulation via the nerve leadingto the effector organ is achieved using energetic modalities, includingelectrical stimulation, magnetic stimulation, acoustic stimulation andothers. In some instances, it is desirable to directly stimulate suchnerve using electrical stimulation. In several embodiments of theinvention, the electrical stimulation is applied at the nerve leading tosmooth muscle, skeletal muscle or is at a ganglion or plexus associatedwith the targeted effector organ. In some embodiments applied to theautonomic system, stimulation is applied directly at the sympathetictrunk or ganglia, celiac ganglion, superior mesenteric ganglion,inferior mesenteric ganglion, or is stimulated at the post-ganglionicnerve. The parasympathetic nervous system has ganglia in close proximityto or located in the organs being innervated, and in some embodimentselectrodes are placed in proximity to these parasympathetic ganglia toachieve the desired simulative effect at the target effector organ.

Peripheral pulse intensity typically ranges is from 5 to 40 mA. In onetriple stimulation bladder embodiment, continuous tsDCS is applied tothe Onuf's nucleus in the sacral region of the spinal cord. The tsDCS isapplied with typical intensity in the range from 2 to 5 mA.

Peripheral pulse intensity typically ranges is from 5 to 40 mA. In onetriple stimulation bladder embodiment, continuous tsDCS is applied tothe Onuf's nucleus in the sacral region of the spinal cord. The tsDCS isapplied with typical intensity in the range from 2 to 5 mA.

In treating bladder dysfunction, the desired subthreshold spinal tsDCSand subthreshold pDCS are established in view of the level at which theeffector organ responds to electrical stimulation, which serves as thethreshold indicator and value of merit. In an embodiment, this level isin a range of 2-5 mA. In an illustrative embodiment, 3-4.5 mAstimulation at the spine and 2-3 mA via the cathetered active peripheralelectrode or 2.5-3.5 mA when applied via abdominal surface electrode,delivers the desired subthreshold peripheral stimulation, assuming thereturn electrode is placed at a bony location. If the peripheral returnelectrode is located closely associated with the bladder, such as byplacement near the bladder or into the bladder, then the threshold isdetected and adjusted accordingly, typically in the same range.

The embodiments described herein provide the basis to treat neurogenicbladder conditions that result in either detrusor hyperreflexia ordetrusor areflexia with external devices, wearable devices, or implanteddevices that deliver the described stimulations. It will be appreciatedby a person skilled in the art that the findings described herein andreduced to practice for bladder modulation using a tsDCS-based approachare directly applicable to controlling kidney, lung, heart, pancreas,gastrointestinal system, stomach, anal sphincter and other autonomicallycontrolled effector organs and may be practiced accordingly under theprincipals disclosed herein. It will now be appreciated that we haveillustrated single, double, and triple stimulation configurations andmethods in practice of embodiments of the invention.

Some of the above described approaches combine a primary stimulationthat modulates either the sympathetic or parasympathetic branch of theautonomic nervous system, with spinal stimulation that amplifies theevoked response. A single constant tsDCS stimulation impacting thetarget effector organ is useful and successful in certain situations. Inother situations, a double-stimulation approach is useful in situationswhere amplifying autonomic outflow at the spinal level is sufficient fora therapeutic effect. In other situations, primary stimulation andspinal stimulation is combined with a third stimulation, which isdelivered at the level of the nerve leading to the targeted effectororgan, to render a useful therapeutic effect. Effector organ stimulationvia the nerve leading to the effector organ is achieved using selectedenergetic modalities, including electrical stimulation, magneticstimulation, acoustic stimulation and others. In some instances, it isdesirable to directly stimulate a nerve using electrical stimulation.The electrical stimulation is directed to the nerve leading to smoothmuscle, skeletal muscle or is at a ganglion or plexus associated withthe ANS. This is directly at the sympathetic trunk or ganglia, celiacganglion, superior mesenteric ganglion, inferior mesenteric ganglion, oris stimulated at the post-ganglionic nerve. The parasympathetic nervoussystem has ganglia in close proximity to or located in the organs beinginnervated, and in some instances electrodes might be placed inproximity to these parasympathetic ganglia.

In another embodiment, stimulation of the motor cortex using TMS or tDCSis combined with spinal stimulation using tsDCS and peripheralstimulation of a nerve leading to a striated muscle under voluntarycontrol. As it relates to bladder dysfunction, this approach can beutilized to strengthen the external urinary sphincter (EUS), which is astriated muscle under voluntary control. In a preferred embodiment, TMSis applied to the motor cortex area associated with the EUS, cathodaltsDCS is applied at the spinal level corresponding to EUS, andperipheral stimulation is applied to the pudendal nerve leading to theEUS using an implanted electrode. In one practice of this embodiment,wherein neural dysfunction of a distal effector organ (e.g., a urinarysphincter) is to be treated, the tsDCS spinal stimulation is applied forthe duration of treatment (a “session”) to the spine at the spinallocation and affecting a neural pathway associated with neural controlof that effector organ, and peripheral and cortical stimulations areapplied to locations associated with that effector organ to improveneural communication to that target effector organ. In anotherembodiment, this approach is applied to the external anal sphincter.

In an illustrative triple stimulation embodiment of the invention,pulsed stimulation and cortical stimulation are applied in the presenceof tsDCS at the spinal location (neural spinal junction) of interest(i.e., a neural spinal junction associated with cortical control of atarget peripheral organ of interest, such as the bladder). The cortical,spinal and peripheral stimulation sites are connected by a common neuralpathway. As applied to the neural pathway, applied peripheralstimulation pulses from a peripheral stimulator device (e.g., device 14)are synchronized with applied cortical stimulation pulses from acortical stimulator 12 or 12A, such that the peripheral pulses precedethe cortical pulse in timing, in any one cycle. In a typical stimulationcycle, at least one peripheral pulse and preferably two, applied to theperipheral location of interest, e.g., a nerve associated with bladdersphincter control, precede a following cortical pulse, wherein suchcortical electrical or magnetic stimulation pulse is applied at acortical location of interest, such as at a cortical site associatedwith control of the target organ, e.g., control of bladder sphincter.Latencies of induced peripheral and cortical pulses are synchronized togive maximal evoked response (MEP), wherein latencies typically rangefrom 20 to 45 ms, and as will be appreciated by a person skilled in theart, the timing of the applied pulses is thus adjusted in view of theselatencies in order to induce the cortical and pulsed neural signals onthe neural pathway of interest as will flow to the spinal junction andoverlap at the spinal junction together in the applied presence of thetsDCS stimulation, to achieve the desired triple stimulation. Peripheralpulse intensity typically ranges from 5 to 40 mA. In one triplestimulation bladder embodiment, the tsDCS is applied to the Onuf'snucleus in the sacral region of the spinal cord. tsDCS with typicalintensity in the range from 2 to 5 mA.

It will be appreciated that in practice of an embodiment of theinvention, we limit maximum current output for double-stimulation withtwo simultaneous skin-surface DC stimulations at or about 5 mA for bothspinal and peripheral stimulation locations. In one embodiment, anillustrative sponge rubber electrode has a skin contact area of 9 cm2resulting in a maximum current density of 0.56 mA/cm2. As will beappreciated by a persons skilled in the art, this is well below thereported safe upper limit for current density of 14.29 ma/cm2 as citedin: Nitsche M A, Liebetanz D, Lang N, Tergau F, Paulus W., in SafetyCriteria For Transcranial Direct Current Stimulation (TDCS) In Humans.Clin Neurophysiol 2003; 114(11):2220e2.”

It will be appreciated that the stimulation routines of the inventionutilizing cortical stimulation, either direct electrical direct currentstimulation or magnetic, as in TMS, follow the triple stimulationteachings of our co-pending U.S. application Ser. No. 14/665,220, filedMar. 23, 2015, entitled: Method and System for Treatment of NeuromotorDysfunction, which is a continuation of now issued U.S. Pat. No.9,011,310, all having a common inventor and assigned to a common owner,and all incorporated herein by reference for all purposes whatsoever.

It will be appreciated that the stimulation teachings of the inventionutilizing double stimulation are an adaptation of the teachings of ourco-pending U.S. application Ser. No. 15/046,797, filed Feb. 18, 2016,entitled: Trans-Spinal Direct Current Modulation Systems, which is acontinuation of now issued U.S. Pat. No. 9,283,391, all having a commoninventor and assigned to a common owner, and all incorporated herein byreference for all purposes whatsoever. In a further alternativeillustrative embodiment of the invention, pulsed implanted stimulationis provided, as is known in the art for other pulsed peripheralapplications. Such stimulation can be set to an output of up to 10.5Vfor pulses up 240 microseconds at 14 Hz, 0.3% duty cycle, providing aset voltage amplitude and adjusting the current to maintain the setamplitude, with pulsed current up to 10 mA. Voltage settings are setaccording to what the patient can tolerate, as will be appreciated by aperson skilled in the art. The current is dependent on the electroderesistance, the electrode tissue interface (likely appreciable) and theimpedance of the tissue itself, is illustratively at around 1 kohm.

In further embodiments of the invention we incorporate a wearable tsDCScontroller that modulates descending autonomic signals traversing thespinal cord. In some embodiments, this is combined with an implantedelectrode that directly stimulates the nerve to a targeted effectororgan. This stimulation is selected as either excitatory or inhibitory,and is further embodiments depends on stimulation frequency as well aspulse amplitude and duration. The implanted electrode is in wirelesscommunication with the wearable tsDCS controller.

This approach is sufficient for certain applications. In otherapplications, it is beneficial to directly modulate central autonomicoutflow before spinal level modulation via tsDCS. In practice of theinvention, we increase or decrease sympathetic outflow, or increase ordecrease parasympathetic outflow, as a person skilled in the art wouldappreciate. Furthermore in particular embodiments we providenon-invasive and non-pharmacological modulating of autonomic outflow forcontrol and treatment of autonomically-related functions and disorders.

Computer

This disclosure includes description by way of example of a deviceconfigured to execute functions (hereinafter referred to as computingdevice) which may be used with the presently disclosed subject matter.The description of the various components of a computing device is notintended to represent any particular architecture or manner ofinterconnecting the components. Other systems that have fewer or morecomponents may also be used with the disclosed subject matter. Acommunication device may constitute a form of a computing device and mayat least include a computing device. The computing device may include aninter-connect (e.g., bus and system core logic), which can interconnectsuch components of a computing device to a data processing device, suchas a processor(s) or microprocessor(s), or other form of partly orcompletely programmable or pre-programmed device, e.g., hard wired andor application specific integrated circuit (“ASIC”) customized logiccircuitry, such as a controller or microcontroller, a digital signalprocessor, or any other form of device that can fetch instructions,operate on pre-loaded/pre-programmed instructions, and/or followedinstructions found in hardwired or customized circuitry to carry outlogic operations that, together, perform steps of and whole processesand functionalities as described in the present disclosure.

In this description, various functions, functionalities and/oroperations may be described as being performed by or caused by softwareprogram code to simplify description. However, those skilled in the artwill recognize what is meant by such expressions is that the functionsresult from execution of the program code/instructions by a computingdevice as described above, e.g., including a processor, such as amicroprocessor, microcontroller, logic circuit or the like.Alternatively, or in combination, the functions and operations can beimplemented using special purpose circuitry, with or without softwareinstructions, such as using Application-Specific Integrated Circuit(ASIC) or Field-Programmable Gate Array (FPGA), which may beprogrammable, partly programmable or hard wired. The applicationspecific integrated circuit (“ASIC”) logic may be such as gate arrays orstandard cells, or the like, implementing customized logic bymetalization(s) interconnects of the base gate array ASIC architectureor selecting and providing metalization(s) interconnects betweenstandard cell functional blocks included in a manufacturer's library offunctional blocks, etc. Embodiments can thus be implemented usinghardwired circuitry without program software code/instructions, or incombination with circuitry using programmed software code/instructions.

Thus, the techniques are limited neither to any specific combination ofhardware circuitry and software, nor to any particular tangible sourcefor the instructions executed by the data processor(s) within thecomputing device. While some embodiments can be implemented in fullyfunctioning computers and computer systems, various embodiments arecapable of being distributed as a computing device including, e.g., avariety of forms and capable of being applied regardless of theparticular type of machine or tangible computer-readable media used toactually effect the performance of the functions and operations and/orthe distribution of the performance of the functions, functionalitiesand/or operations.

The interconnect may connect the data processing device to define logiccircuitry including memory. The interconnect may be internal to the dataprocessing device, such as coupling a microprocessor to on-board cachememory or external (to the microprocessor) memory such as main memory,or a disk drive or external to the computing device, such as a remotememory, a disc farm or other mass storage device, etc. Commerciallyavailable microprocessors, one or more of which could be a computingdevice or part of a computing device, include a PA-RISC seriesmicroprocessor from Hewlett-Packard Company, an 80×86 or Pentium seriesmicroprocessor from Intel Corporation, a PowerPC microprocessor fromIBM, a Sparc microprocessor from Sun Microsystems, Inc, or a 68xxxseries microprocessor from Motorola Corporation as examples.

The inter-connect in addition to interconnecting such asmicroprocessor(s) and memory may also interconnect such elements to adisplay controller and display device, and/or to other peripheraldevices such as input/output (I/O) devices, e.g., through aninput/output controller(s). Typical I/O devices can include a mouse, akeyboard(s), a modem(s), a network interface(s), printers, scanners,video cameras and other devices which are well known in the art. Theinter-connect may include one or more buses connected to one anotherthrough various bridges, controllers and/or adapters. In one embodimentthe I/O controller includes a USB (Universal Serial Bus) adapter forcontrolling USB peripherals, and/or an IEEE-1394 bus adapter forcontrolling IEEE-1394 peripherals.

The memory may include any tangible computer-readable media, which mayinclude but are not limited to recordable and non-recordable type mediasuch as volatile and non-volatile memory devices, such as volatile RAM(Random Access Memory), typically implemented as dynamic RAM (DRAM)which requires power continually in order to refresh or maintain thedata in the memory, and non-volatile RAM (Read Only Memory), and othertypes of non-volatile memory, such as a hard drive, flash memory,detachable memory stick, etc. Non-volatile memory typically may includea magnetic hard drive, a magnetic optical drive, or an optical drive(e.g., a DVD RAM, a CD RAM, a DVD or a CD), or ‘other type of memorysystem which maintains data even after power is removed from the system.

For the purposes of describing and defining the present teachings, it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that may be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation may vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

While these teachings have been described in terms of specificembodiments, it is evident in view of the foregoing description thatnumerous alternatives, modifications and variations will be apparent tothose skilled in the art. Accordingly, these teachings are intended toencompass all such alternatives, modifications and variations which fallwithin the scope and spirit of the present teachings and the followingclaims. The foregoing description is illustrative validation of thepresent invention. It will now be appreciated that tsDCS stimulationaccording to embodiments of the invention can be practicednon-invasively or invasively using direct current stimulation tomodulate spinal cord neurons. While these teachings have been describedin terms of specific embodiments, it is evident in view of the foregoingdescription that numerous alternatives, modifications and variationswill be apparent to those skilled in the art. Accordingly, theseteachings are intended to encompass all such alternatives, modificationsand variations which fall within the scope and spirit of the presentteachings and the following claims.

What is claimed is:
 1. A system for modulating activity of anautonomically-innervated effector organ in a vertebrate being, thesystem comprising: a first housing including a first DC power sourcethat provides direct current between power terminals of oppositepolarity; a first stimulation component including a spinal stimulationcircuit coupled to the power terminals and having an identified spinalsignal output connection and an identified spinal reference connection,both on said housing, and configured to provide a constant directcurrent spinal stimulation signal between a first active electrodelocated at a spinal location associated with efferent neural outflow tothe autonomically-innervated effector organ and a second returnelectrode for spinal direct current stimulation associated withmodulation of the activity of the autonomically-innervated effectororgan; a second housing including a second DC power source that providesdirect current between power terminals of opposite polarity; and asecond stimulation component including a neural stimulation circuitcoupled to the power terminals of the second DC power source and havingan identified neural signal output connection and an identified neuralreference connection, both connections on said housing, that provides aconstant direct current neural stimulation signal between thirdelectrode and a fourth electrode configured to be attached across asection of a nerve associated with the autonomically-innervated effectororgan.
 2. The system of claim 1, wherein said autonomically-innervatedeffector organ is the bladder.
 3. The system of claim 2, wherein saidspinal location is at spinal level S2-S4 or at spinal level T11-L2. 4.The system of claim 1, wherein said second electrode is positioned at anexterior abdominal location or iliac crest.
 5. The system of claim 1,wherein at least one of the first electrode and the second electrode isimplanted.
 6. The system of claim 1, wherein said second electrode ispositioned within the bladder trans-urethrally.
 7. The system of claim1, wherein said system is implanted.
 8. The system of claim 1, furthercomprising an implanted feedback device.
 9. The system of claim 1,wherein said autonomically-innervated effector organ is the bladder andsaid implanted feedback device is a bladder pressure sensor.
 10. Thesystem of claim 1, wherein said signal-providing component istranscranial direct current stimulation.
 11. The system of claim 1,wherein said signal-providing component is transcutaneous vagal nervestimulation.
 12. The system of claim 1, wherein said signal-providingcomponent is transcranial magnetic stimulation.
 13. The system of claim1, wherein said signal-providing component is temperature stimulation.14. The system of claim 1, wherein said signal-providing component is apharmacological agent.
 15. The system of claim 1, wherein said first DCpower source communicates wirelessly with said second DC power source.16. A method for modulating activity of an autonomically-innervatedeffector organ in vertebrate beings, the method comprising: applying asource of direct current to a spinal location associated with efferentneural outflow to the autonomically-innervated effector organ.
 17. Themethod of claim 16, further comprising: applying a source of pulseddirect current to a nerve providing neural control of muscles of theautonomically-innervated effector organ.
 18. The method of claim 17,further comprising: modulating central autonomic outflow.
 19. The methodof claim 16, further comprising: modulating central autonomic outflow.20. The method of claim 16, wherein the activity of anautonomically-innervated effector organ is bladder function.